Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet

Abstract

ObjectiveElevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown.MethodsK14–VEGFR-3–Ig (sR3) mice that constitutively express soluble-VEGFR-3–Ig in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow or high-fat diet for 20 weeks. To assess the effect of VEGFR-3 blockage on adipose tissue growth and insulin sensitivity, we evaluated weight gain, adipocyte size and hepatic lipid accumulation. These results were complemented with insulin tolerance tests, FACS analysis of adipose tissue macrophages, in vitro 3T3-L1 differentiation assays and in vivo blocking antibody treatment experiments.ResultsWe show here that sR3 mice are protected from obesity-induced insulin resistance and hepatic lipid accumulation. This protection is associated with enhanced subcutaneous adipose tissue hyperplasia and an increased number of alternatively-activated (M2) macrophages in adipose tissue. We also show that VEGF-C and -D are chemotactic for murine macrophages and that this effect is mediated by VEGFR-3, which is upregulated on M1 polarized macrophages. Systemic antibody blockage of VEGFR-3 in db/db mice reduces adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity.ConclusionsThese results reveal an unanticipated role of the lymphangiogenic factors VEGF-C and -D in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance.

Obesity, But Not High Fat Diet, Impairs Lymphatic Function

“…25,26 Consistent with these studies and our finding of increased macrophage infiltration in obese mice, we noted a marked increase in VEGF-C expression in both serum (1.75-fold) and skin (2-fold) of HFD-fed obese C57BL/6J mice, as compared with their NCD-fed controls (Figures 3c and d). In addition, analysis of skin tissues from obese HFD-fed C57BL/6J mice also demonstrated increased expression of inflammatory cytokines including TNF-α (20-fold) and IL-1β (8.32-fold) as compared with their NCD controls (Figures 3e and f).…”

“…This effect has a key role on glucose homeostasis in obesity by regulating macrophage infiltration and differentiation. 25 In addition, the combination of increased VEGF-C in the context of decreased LEC VEGFR-3 expression in obese mice suggests that homeostatic mechanisms contribute to changes in VEGF-C expression. This scenario may be similar to insulin resistance in obesity (that is, increased insulin/decreased insulin receptor function), suggesting that similar mechanisms regulate lymphatic function, a condition we have termed VEGF-C resistance.…”

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

“…Whole mounts were produced as described (Karaman et al, 2015) with the following modifications. Retinas of Sema3a +/lacZ P7 pups were dissected after fixation and stained overnight.…”

Aspectos oxidativos da síndrome metabólica e aterosclerose

“…Estudos mostram que o ganho de peso aumenta a formação de substâncias pró-oxidantes e também mostram que indivíduos obesos tem perfil oxidativo acentuado quando comparados a indivíduos normais. A obesidade tem relação com outros estados mórbidos (hipertensão arterial, resistência à insulina, DM2, dislipidemia e complicações vasculares) que possuem relação com o desencadeamento do desbalanço oxidativo [39][40][41].…”

“…Também se observa aumento da expressão de NADPH-oxidase, que está diretamente associada ao estresse oxidativo [3,34,41,42].…”